Uveal melanoma (UM) is the most common intraocular malignancy in the United States and has a 10-year disease specific survival rate of 50%. No effective treatment options exist. Mutations in known melanoma oncogenes such as BRAF, NRAS, or KIT that prevail in cutaneous and mucosal melanoma are absent in UM. We recently identified somatic mutations in the heterotrimeric G protein alpha q subunits, GNAQ and GNA11, in over 80% of uveal melanomas. The constitutively activating mutations occur in a mutually exclusive pattern. The proportion of GNA11 mutant tumors increases with progression stage, suggesting that mutant GNA11 is a more potent oncogene. The mutations activate GNAQ and GNA11, but inactivating their GTPase activity similar to ras activation making it difficult to target them directly with small molecules. Therefore, it is paramount to characterize their respective downstream effector pathways to identify opportunities for targeted therapy. Both PKC/MAP-kinase and YAP pathways contribute to oncogenic GNAQ mediated tumorigenesis. However, the details of their activation are incompletely understood, and therapeutic targeting of those pathway shows limited therapeutic efficacy indicating that other oncogenic effector pathways might be involved. Therefore, there is a strong need to better delineate the signaling cascades triggered by oncogenic GNAQ and GNA11, explore the mechanism of adaptive resistance to pathway inhibition, and to identify additional therapeutic targets to develop a refined therapeutic strategy. In this project, we will fill this gap and investigate the three overlapping areas by using both candidate and unbiased approaches: in Aim 1, we will fill in the emerging signal network downstream of oncogenic GNAQ proteins to identify therapeutic targets. In Aim 2, we will investigate the factors that render GNA11 a more potent uveal melanoma oncogene compared to GNAQ. In Aim 3, we will validate therapeutic targets identified in Aims 1 and 2 using pre-clinical models, identify the mechanism of adaptive resistance to targeted therapy and identify synergisms between therapeutic approaches with the goal to develop improved therapeutic combination strategies for patients.